Leukocyte adhesion to endothelium and migration into tissues is critically dependent on specific interactions of adhesion receptors on the leukocytes, particularly members of the CD11/CD18 family, with ligands on the endothelial cells such as intercellular adhesion molecule-1 (ICAM-1) and endothelial-leukocyte adhesion molecule (ELAM). Recent studies have shown that ICAM-1 is also expressed on skin and respiratory epithelium, and that its expression may increase in inflammatory conditions. In particular, in a monkey model of asthma, ICAM-1 expression on surface epithelial cells in tracheal sections increased after repeated antigen inhalation, and anti- ICAM-1 monoclonal antibodies blocked adhesion of eosinophils as well as the increase in airway reactivity associated with this antigen exposure. Our own studies have shown that increased neutrophil adhesion to a human tracheal cell line vs. primary cell cultures is correlated with increased ICAM-1 expression and can be blocked by anti-ICAM antibodies. We have also shown that viral infection of human tracheal cells in vitro also increased CD11/CD18 dependent neutrophil adherence, but that this was not blocked by anti-ICAM-1, suggesting that another adhesion ligand(s) is involved. In this project, we propose a comprehensive investigation of the role of the CD11/CD18 complex and its corresponding ligands in human airway disease. We will test the hypotheses that ICAM-1 expression on human airway cells is increased following inflammatory stimuli in vivo and in vitro, and that other adhesion-promoting ligands in addition to ICAM-1 are also involved. Our specific aims are to: 1) Develop new monoclonal antibodies to ICAM-1; 2) use immunohistochemical and cell sorter analyses to determine ICAM expression on human nasal and bronchial cells from a variety of airway diseases; to determine the extent of CD11/CD18 expression on inflammatory cells in these specimens; and to determine the effects of antigen, cold air, and exercise challenge on ICAM expression; 3) define the effects of cytokines and other inflammatory mediators on neutrophil adhesion and ICAM expression in vitro and determine if lavage fluids from patients with increased ICAM expression in vivo also increase ICAM expression in vitro; and 4) use an immunoaffinity sandwich technique to isolate and characterize adhesion ligands other than ICAM-1 from human airway cells in vitro. The results of these studies should greatly increase our understanding of the role of CD11/CD18 and ICAM's in airway diseases, and may suggest optimal strategies for the therapeutic use of adhesion antagonists.